The overall objective of this program project is to better understand mechanisms involved in the pathogenesis of macrovascular disease in diabetes, which is the major cause of morbidity and mortality in both type 1, and especially type 2 diabetes. Its goal is to better understand the genetic, cellular, biochemical and molecular nature of the premature atherosclerosis that characterizes the diabetic state. The program project is comprised of 4 inter-related projects and 3 cores. Project 17 will study the interaction of atherogenic lipoproteins with extracellular matrix molecules that result in the retention of these lipoproteins in the vascular wall, thereby enhancing atherosclerosis. It will focus on the regulation of these matrix molecules by factors associated with the diabetic state that facilitate lipoprotein retention. Project 21 is aimed at understanding why a subgroup of intensively-treated patients with type 1 diabetes develop features of type 2 diabetes such as central obesity, insulin resistance, and the associated cardiovascular risk factors that put these individuals at increased risk of premature cardiovascular and renal disease. Project 18 will study the role of diabetes on the regulation of the newly described cellular transporter, ABCA1, which plays a critical role in reverse cholesterol transport. Defects in the ability to remove cholesterol from the artery wall can result in increased atherogenesis. Project 20 will study the biochemical pathways involved in glycation and glycoxidation reactions that play a role in damaging various vascular lipids and proteins, thereby accelerating atherosclerosis in diabetes. These projects will be supported by an administrative and 2 scientific cores: The Arterial Tissue and Applied Pathology Core will provide 3 of the projects with arterial tissue from human subjects with diabetes and from several animal models. The Protein Chemistry Core will provide sophisticated biochemical support for the in vitro and in vivo studies proposed in all the projects. The increased understanding of the pathogenesis of the premature vascular disease in diabetes that will be derived from each of the projects has important therapeutic implications for the prevention and treatment of macrovascular disease in diabetes.